Increased vitamin D receptor level enhances 1,25-dihydroxyvitamin D-3-mediated gene expression and calcium transport in Caco-2 cells

Altered vitamin D receptor (VDR) level has been proposed to explain differe nces in intestinal responsiveness to 1,25-dihydroxyvitamin D-3 [1,25(OH)(2) D-3], We tested whether the enterocyte VDR level influences 1,25(OH)(2)D-3- mediated gene expression and transepithelial calcium (Ca) transport in the human intestinal cell line Caco-2, Cells were stably transfected with a hum an metallothionein (hMT) IIA promoter-human VDR (hVDR) complementary DNA (c DNA) transgene that overexpressed hVDR in response to heavy metals. In MTVD R clones, induction of 25-hyroxyvitamin D-3-24-hydroxylase (24-OHase) messe nger RNA (mRNA) expression by 1,25(OH)(2)D-3 (10(-9) M, 4 h) was correlated to metal-induced changes in nuclear VDR level (r(2) = 0.99), In MTVDR clon es, basal VDR level was 2-fold greater and 1,25(OH)(2)D-3-mediated Ca trans port (10(-7) M, 24 h) was 43% higher than in parental Caco-2 cells. Treatme nt of MTVDR clones with Cd (1 muM, 28 h) increased VDR level by 68%, signif icantly enhanced 1,25(OH)(2)D-3-mediated Ca transport by 24%, and increased accumulation of calbindin D-9K mRNA by 76% relative to 1,25(OH)(2)D-3 alon e. These observations support the hypothesis that the enterocyte VDR level is an important modulator of intestinal responsiveness to 1,25(OH)(2)D-3.